Impact of the lesion procedure on the profiles of motor impairment and molecular responsiveness to L-DOPA in the 6-hydroxydopamine mouse model of Parkinson's disease

6-Hydroxydopamine (6-OHDA) lesions are being used in the mouse for basic research on Parkinson's disease and L-DOPA-induced dyskinesia. We set out to compare unilateral lesion models produced by intrastriatal or intramesencephalic injections of a fixed 6-OHDA concentration (3.2 mu g/mu l) in C57BL/6 mice. In the first experiment, toxin injections were performed either at two striatal coordinates (1 or 2 mu l per site, termed striatum(2 x 1 mu l) and striatum(2 x 2 mu l) models), in the medial forebrain bundle (MFB), or in the substantia nigra pars compacta (SN) (1 mu l per site). All the four lesion models produced significant forelimb use asymmetry, but spontaneous turning asymmetry only occurred in the MFB and striatum(2 x 2 mu l) models. After the behavioral studies, the induction of phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK1/2) by acute L-DOPA (30 mg/kg) was used as a marker of post-synaptic supersensitivity. Striatal pERK1/2 expression was sparse in the SN and striatum(2 x 1 mu l) groups, but pronounced in the striatum(2 x 2 mu l) and MFB-lesioned mice. In further experiments, mice with MFB and striatal(2 x 2 mu l) lesions were used to compare behavioral and molecular responses to chronic L-DOPA treatment (12 days at 3 and 6 mg/kg/day). Maximally severe abnormal involuntary movements (AIMS) occurred in all MFB-lesioned mice, whereas only 35% of the mice with striatal lesions developed dyskinesia. Striatal tissue levels of dopamine were significantly lower in the dyskinetic animals (both MFB and striatum(2 x 2 mu l) groups) in comparison with the non-dyskinetic ones. Noradrenaline levels were significantly reduced only in MFB lesioned animals and did not differ among the dyskinetic and non-dyskinetic cases with striatal lesions. In all groups, the L-DOPA-induced AIM scores correlated closely with the number of cells immunoreactive for tyrosine hydroxylase or FosB/Delta FosB in the striatum. In conclusion, among the four lesion procedures examined here, only the MFB and striatum(2) (x 2 mu l) models yielded a degree of dopamine denervation sufficient to produce spontaneous postural asymmetry and molecular supersensitivity to L-DOPA. Both lesion models are suitable to reproduce L-DOPA-induced dyskinesia, although only MFB lesions yield a pronounced and widespread expression of post-synaptic supersensitivity markers in the striatum. (c) 2011 Elsevier Inc. All rights reserved.